U.S. patent number 5,132,117 [Application Number 07/463,339] was granted by the patent office on 1992-07-21 for aqueous core microcapsules and method for their preparation.
This patent grant is currently assigned to Temple University. Invention is credited to Tully J. Speaker, Mani R. Sundararajan.
United States Patent |
5,132,117 |
Speaker , et al. |
July 21, 1992 |
Aqueous core microcapsules and method for their preparation
Abstract
A microcapsule comprising an aqueous core, and capsular membrane
formed from the interfacial reaction product of a hydrophilic
polymeric Lewis acid or salt thereof with a lipophilic Lewis base
or salt thereof.
Inventors: |
Speaker; Tully J.
(Philadelphia, PA), Sundararajan; Mani R. (Bryn Mawr,
PA) |
Assignee: |
Temple University
(Philadelphia, PA)
|
Family
ID: |
23839762 |
Appl.
No.: |
07/463,339 |
Filed: |
January 11, 1990 |
Current U.S.
Class: |
424/490; 264/4.1;
264/4.7; 424/493; 428/402.2; 428/402.21 |
Current CPC
Class: |
A61K
9/5089 (20130101); B01J 13/16 (20130101); Y10T
428/2984 (20150115); Y10T 428/2985 (20150115) |
Current International
Class: |
A61K
9/50 (20060101); B01J 13/16 (20060101); B01J
13/06 (20060101); B01J 013/16 (); A61K
009/50 () |
Field of
Search: |
;264/4.1,4.3,4.7
;428/402.2,402.21 ;424/490,493 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
|
|
|
|
|
|
|
1091077 |
|
Nov 1967 |
|
GB |
|
1091078 |
|
Nov 1967 |
|
GB |
|
Other References
Exploration of some major pharmaceutical Technologic
Characteristics of Aqueous Core, Salt-walled Microcapsules, 1988,
Mani Raj Sundararajan, thesis..
|
Primary Examiner: Maples; John S.
Assistant Examiner: Covert; John M.
Attorney, Agent or Firm: Ratner & Prestia
Claims
We claim:
1. A microcapsule comprising an aqueous core, and a capsular,
ionically-stabilized, anisotropic Lewis salt membrane formed from
the interfacial reaction product of an emulsion of an aqueous
solution of a water-soluble, hydrophilic polymeric Lewis acid or
salt thereof with a non-aqueous solution of a lipophilic Lewis base
or salt thereof, wherein said Lewis base or salt thereof is
selected from the group consisting of hexylamine, stearylamine,
piperidine, triethylamine, hexanediamine, triethylenediamine,
benzalkonium chloride, cetylpyridinium chloride,
hexamethylrosanilium chloride and tetramethylrosanilium
chloride.
2. A microcapsule of claim 1 in which the solvent of said
non-aqueous solution is selected from cyclohexane, chloroform,
n-butyl chloride, methylisobutyl ketone, chloroform/cyclohexane
(1:4 vol%), dichloromethane/cyclohexane (1:4 vol %), and
n-hexane/n-heptane (1:1 vol %).
3. A microcapsule of claim 1 in which the Lewis acid is selected
from polyuronic acids and acidic resins.
4. A microcapsule of claim 1 in which the Lewis acid is selected
from acacia, arabic acid, agar, carboxymethylcellulose, ghatti gum,
guar gum, polyacrylic acid, polyacrylic acid/polyoxyethylene
copolymer, and sterculia gum.
5. A microcapsule of claim 1 in which the Lewis acid salt is
selected from sodium carboxymethylcellulose, sodium polyacrylate,
sodium polyacrylate cross-linked with polyoxyethylene, and sodium
alginate.
6. A microcapsule of claim 1 in which an active ingredient is
dissolved or suspended within the aqueous core.
7. A microcapsule of claim 6 in which the active ingredient is FD
& C Red No. 1, FD & C Red No. 40, or sodium
fluorescein.
8. A microcapsule of claim 6 in which the active ingredient is a
pharmaceutical.
9. A microcapsule of claim 8 in which the pharmaceutical is an
anti-asthmatic or anti-neoplastic.
10. A microcapsule of claim 8 in which the pharmaceutical is
selected from the group consisting of theophylline, doxorubicin,
deferoxamine, and terbutaline.
11. A microcapsule comprising the ionically-stabilized, aniostropic
Lewis salt reaction product of
a) an emulsion of an aqueous solution of a polyfunctional Lewis
acid or acid salt, a core material, an emulsifying agent, and a
first non-aqueous solvent; and
b) a polyfunctional Lewis base or basic salt dissolved in a second
non-aqueous solvent soluble in said first non-aqueous solvent,
wherein said Lewis base or salt thereof is selected from the group
consisting of hexylamine, stearylamine, piperidine, triethylamine,
hexanediamine, triethylenediamine, benzalkonium chloride,
cetylpyridinium chloride, hexamethylrosanilium chloride and
tetramethylrosanilium chloride.
12. A microcapsule of claim 11 in which said first and second
non-aqueous solvents are the same.
13. A microcapsule of claim 11 in which the emulsifying agent is
sorbitan trioleate.
14. A microcapsule of claim 11 in which the non-aqueous solvents
are selected from cyclohexane, chloroform, n-butyl chloride,
methylisobutyl ketone, chloroform/cyclohexane (1:2 vol %),
dichloromethane/ cyclohexane (1:4 vol %), and n-hexane/n-heptane
(1:1 vol %).
15. A microcapsule of claim 11 in which the Lewis acid is selected
from polyuronic acids and acidic resins.
16. A microcapsule of claim 11 in which the Lewis acid is selected
from acacia, arabic acid, agar, carboxymethylcellulose, ghatti gum,
guar gum, polyacrylic acid, polyacrylic acid/polyoxyethylene
copolymer, and sterculia gum.
17. A microcapsule of claim 11 in which the Lewis acid salt is
selected from sodium carboxymethylcellulose, sodium polyacrylate,
sodium polyacrylate cross-linked with polyoxyethylene, and sodium
alginate.
18. A microcapsule of claim 11 in which the core material is FD
& C Red No. 1, FD & C Red No. 40, or sodium
fluorescein.
19. A microcapsule of claim 11 in which the core material is a
pharmaceutical.
20. A microcapsule of claim 19 in which the pharmaceutical is an
anti-asthmatic or anti-neoplastic.
21. A microcapsule of claim 19 in which the pharmaceutical is
selected from the group consisting of theophylline, doxorubicin,
deferoxamine, and terbutaline.
22. A process for preparing aqueous core microcapsules having a
capsular, ionically-stabilized, anisotropic Lewis salt membrane,
comprising the steps of:
a) dissolving a polyfunctional Lewis acid or salt thereof in
water;
b) dissolving or suspending a core material in water;
c) emulsifying the solutions of steps a) and b) in a first
non-aqueous solvent containing a surfactant to form an
emulsion;
d) dissolving a polyfunctional Lewis base or salt in a second
non-aqueous solvent soluble in said first non-aqueous solvent,
wherein said Lewis base or salt thereof is selected from the group
consisting of hexylamine, stearylamine, piperidine, triethylamine,
hexanediamine, triethylenediamine, benzalkonium chloride,
cetylpyridinium chloride, hexamethylrosanilium chloride and
tetramethylrosanilium chloride;
e) adding the Lewis base solution to the emulsion, with stirring;
and
f) harvesting the microcapsules.
23. A process of claim 22 in which the non-aqueous solvents are
selected from cyclohexane, chloroform, n-butyl chloride,
methylisobutyl ketone, chloroform/cyclohexane (1:4 vol %),
dichloromethane/ cyclohexane (1:4 vol %) and n-hexane/n-heptane
(1:1 vol %)
24. A process of claim 22 in which the Lewis acid is selected from
polyuronic acids and acidic resins.
25. A process of claim 22 in which the Lewis acid is selected from
acacia, arabic acid, agar, carboxymethylcellulose, ghatti gum, guar
gum, polyacrylic acid, polyacrylic acid/polyoxyethylene copolymer,
and sterculia gum.
26. A process of claim 22 in which the Lewis acid salt is selected
from sodium carboxymethylcellulose, sodium polyacrylate, sodium
polyacrylate cross-linked with polyoxyethylene, and sodium
alginate.
27. A process of claim 22 further comprising the steps of
centrifuging to harvest the microcapsules, resuspending the
microcapsules in a non-aqueous solvent, repeating the
centrifuging/resuspending steps at least once, and lyophilizing the
microcapsules.
28. A process of claim 22 in which the surfactant is from about 7%
to about 20% sorbitan trioleate by volume of non-aqueous
solvent.
29. A process of claim 22 in which the volume fraction of aqueous
phase is from about 0.2 to about 0.6.
30. A process of claim 22 in which said first and second
non-aqueous solvents are the same.
31. A process of claim 29 in which the Lewis base or salt thereof
is first dissolved in the non-aqueous solvent and the remaining
materials are emulsified therein.
Description
FIELD OF THE INVENTION
This invention relates to novel microcapsules having an anisotropic
salt membrane encapsulating an aqueous or substantially aqueous
core. The microcapsules are prepared by the interfacial reaction of
Lewis acid and base wall-forming reactants.
BACKGROUND OF THE INVENTION
Microencapsulation is a process by which a relatively thin coating
can be applied to dispersions of small particles of solids or
droplets of liquids, thus providing a means for converting liquids
to solids, altering colloidal and surface properties, providing
environmental protection, and controlling the release
characteristics or availability of coated materials. Several of
these properties can be attained by macropackaging techniques;
however, the uniqueness of microencapsulation is the smallness of
the coated particles and their subsequent use and adaptation to a
wide variety of dosage forms and product applications, which
heretofore may not have been feasible technically.
INFORMATION DISCLOSURE STATEMENT
U.S. Pat. No. 3,137,631 relates to encapsulation of water insoluble
organic liquids by cross-linking synthetic resins through the
application of heat or catalysts or both. The capsule shells are
described as formed from covalently linked non-ionic materials or
from heat denaturable proteins. The resultant capsules benefit from
secondary treatment with cross-linking agents to impart increased
stability to the capsule.
U.S Pat. No. 4,205,060 discloses microcapsules comprising a core
containing a water soluble salt formed by reaction between a
polymeric ionic resin and a medicament, formed either by reaction
of an acidic polymer with a basic medicament or, conversely, a
basic polymer with an acidic drug. The walls of the microcapsules
are formed from water-insoluble film-forming polymers. The
water-insoluble film-forming polymers identified as suitable
sheathing agents are all neutral non-ionized polymers. The capsules
of that invention are made by preparing an aqueous solution of a
salt made by reacting a medicament and a core polymer; preparing a
solution of a water-insoluble sheath-forming polymer in a first
water-immiscible organic liquid; dispersing the aqueous solution in
the organic solution; and adding to the dispersion a second
water-immiscible liquid which is a non-solvent for the
sheath-forming polymer to precipitate the film around droplets of
the dispersed aqueous phase.
U.S. Pat. No. 4,606,940 discloses the preparation of microcapsules
by coacervation to precipitate the encapsulating material. A single
colloid is dispersed in water and the water of solvation is removed
from around the colloid by addition of chemical compounds which
have a greater affinity for water than the colloid. This causes the
colloid chains to come closer together and form the coacervate.
Temperature changes are needed to facilitate the encapsulation by
coacervation.
U.S. Pat. No. 3,959,457 discloses microcapsules comprised of the
reaction product produced in a finely dispersed emulsion of a
water-immiscible solution of (a) an organic polyfunctional Lewis
base, in a (b) low boiling point, polar, organic solvent, and an
aqueous solution of a (c) partially hydrophilic, partially
lipophilic, polyfunctional Lewis acid. The capsules of that
invention have lipophilic cores.
SUMMARY OF THE INVENTION
It is an object of this invention to provide stable microcapsules
having aqueous cores. It is a further object of this invention to
provide a high efficiency method of encapsulation.
The microcapsules of this invention consist of aqueous or
substantially aqueous cores surrounded by capsular anisotropic
Lewis salt membranes.
The aqueous-core microcapsules of this invention may be prepared by
dispersing an aqueous solution of a suitable Lewis-acid
wall-forming reactant and a core material in a suitable non-aqueous
solvent, adding an additional amount of non-aqueous solvent
containing a suitable Lewis-base wall-forming reactant, and
harvesting the microcapsules formed by the interfacial
reaction.
Alternatively, the aqueous-cored microcapsules of this invention
may be prepared by dispersing an aqueous solution of a suitable
Lewis-acid wall-forming reactant and a core material in a suitable
non-aqueous solvent containing a suitable Lewis-base wall-forming
reactant and harvesting the microcapsules formed by the interfacial
reaction.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the first of the alternatives described above,
the Lewis salt-walled aqueous-cored microcapsules of this invention
are prepared by the general scheme described below. The capsular
membrane is an ionically-stabilized, anisotropic Lewis salt
membrane.
An aqueous solution of a suitable Lewis polyacid macromolecule or
salt thereof is prepared. Suitable Lewis polyacids are
polyfunctional electron pair acceptors including, but not limited
to polyuronic acids and acidic resins, such as acacia, arabic acid,
agar, carboxymethylcellulose, ghatti gum, guar gum, polyacrylic
acid, polyacrylic acid/polyoxyethylene copolymer, and sterculia
gum. Examples of Lewis polyacid salts are sodium
carboxymethylcellulose, sodium polyacrylate, sodium polyacrylate
cross-linked with polyoxyethylene, and sodium alginate. The choice
of Lewis polyacid is a matter of preference and should be apparent
to one skilled in the art. The acidic macromolecule must be water
soluble. Typical concentrations of polyacid in water are from 1 to
20% by weight.
An aqueous solution or suspension of the desired core material is
added to the aqueous solution of Lewis polyacid or salt prepared
above. Alternatively, the desired core material is added directly
to the Lewis polyacid solution. Both dissolved and suspended
substances may be incorporated by the process of this invention
provided that they do not interfere with the encapsulating process
and do not react with or dissolve the capsular membrane. Effective
amounts of core materials depend entirely on the type and
characteristics of the core material, the capsular membrane
thickness and on the intended utility of the product. Among the
materials which have been encapsulated by the process of this
invention are FD & C (Food, Drug and Cosmetic) Red No. 40, FD
& C Red No. 1, doxorubricin hydrochloride, sodium fluorescein,
sodium methotrexate, theophylline, deferoxamine, 5-fluorouracil,
nicotinamide, terbutaline, and water.
A water-in-oil emulsifying agent, such as sorbitan trioleate, or a
blend of emulsifying agents is dissolved in an organic solvent. The
organic solvent, which may be a mixture, is selected from those
solvents having a composite Hildebrand solubility parameter value
of approximately 17 MPa.sup.1/2, with the proviso that no single
component be substantially miscible with water. An alternative
criterion is that the solvent have Hildebrand-Hansen dispersion,
dipole, and hydrogen bonding parameters of about 14, 15 and less
than about 7 MPa.sup.1/2, respectively, again with the proviso that
no single component be substantially miscible with water. While the
Hildebrand-Hansen values are useful tools in selecting organic
solvents, the solvents must be tested as there are some which are
not useful if selected on this basis alone. Some solvents and
solvent combinations which have been found useful in the practice
of this invention are set forth in Table 1 below:
TABLE 1 ______________________________________ SOLVENT &
HILDEBRAND-HANSEN SOLVENT BLENDS MPa.sup.1/2 VALUES
______________________________________ n-Butyl chloride 17.1 (neat)
Methyl isobutyl ketone 17.6 (neat) Cyclohexane .apprxeq.16.8 (neat)
Dichloromethane & cyclohexane .apprxeq.17 (1:4) Hexane &
n-heptane 15.1 (1:1) Cyclohexane & chloroform 17.2 (4:1)
______________________________________
Chloroform itself is another example of a solvent useful in this
invention.
The aqueous solution o a Lewis polyacid or a suitable salt of a
Lewis polyacid and core material is dispersed in the organic
solvent containing the emulsifying agent, forming an emulsion.
Generally, for each volume of aqueous solution, form 0.5 to 4.0
volumes of a 7% to 20% (by volume) emulsifying agent/organic
solvent solution are used.
A suitable Lewis base or salt thereof is dissolved in the same
organic solvent as used for preparation of the emulsion. Suitable
Lewis bases include primary, secondary, and tertiary amines,
bis-primary amines, and bis-secondary amines. Among the bases found
useful in the practice of this invention are hexylamine,
stearylamine, piperidine, triethylamine, hexanediamine, and
triethylenediamine. Examples of suitable Lewis base salts are
benzalkonium chloride, cetylpyridinium chloride,
hexamethylrosanilium chloride, and tetramethylrosanilium chloride.
Suitable Lewis bases and salts are not limited to those enumerated.
Many Lewis bases are good wall-forming components, excepting those
weakly basic compounds with high water solubility, such as
tromethamine.
In general, any of the preferred free polyacids may be paired with
any of the preferred free bases to form an effective pair of
wall-forming reactants. Similarly, in general, any of the preferred
salts of polyacids may be combined with any of the salts of bases
to form a useful pair of wall-forming reactants. However, combining
a free polyacid with the salt of a base or a free base with a salt
of a polyacid generally results in lowered yields of finished
microcapsules.
To form the microcapsules an amount of the Lewis base/organic
solvent solution containing a stoichiometric amount of base
equivalent to the amount of acid, is added to the acid/core
material/water/organic solvent emulsion prepared above, while
stirring vigorously. The resultant microcapsules are harvested by
methods well known to those skilled in the art, as exemplified
below.
It is convenient to centrifuge the suspension to speed separation
of microcapsules from the phase comprising the non-aqueous solvent
blend. The microcapsules may be separated more completely from the
manufacturing fluid by a variety of means. The remaining
non-aqueous solvent may be removed by volatilization, with or
without the aid of externally applied heat or lowered pressure.
Alternatively the remaining solution of surfactant in solvent blend
may be removed by suspension of the microcapsule phase in a
convenient diluting volume of cyclohexane or similar miscible
solvent and harvesting, e.g. as by centrifugation, one or more
times. The remaining solution of surfactant in non-aqueous solvent
may be removed by both dilution and harvesting and volatilization;
or any remaining unencapsulated aqueous solution may be removed by
aspiration of the separated bulk aqueous phase; or any remaining
unencapsulated aqueous phase may be removed by suspension of the
microcapsule phase in a convenient diluting volume of water and
harvesting, as by centrifugation, one or more times; or any
remaining unencapsulated aqueous solution may be removed by
aspiration of the separated bulk aqueous phase, suspension of the
microcapsule phase in a convenient diluting volume of water and
harvesting, as by centrifugation, one or more times.
Depending in part on the degree to which manufacturing fluid is
removed and in part on the nature of the core solute, the aqueous
core microcapsules may be collected as a free-flowing suspension, a
viscid flowable concentrate, a paste, a friable flake or, with
further treatment, as a lyocake. Lyophilization is particularly
desired to provide stable microcapsules with highly water soluble
core materials.
Under optimal conditions high efficiencies of encapsulation of the
aqueous phase are obtained. These optimal conditions are dependent
on several variables including the ratio of aqueous to non-aqueous
manufacturing solvent phases and the concentration of surfactant
employed. For example, the yield of aqueous core microcapsules with
walls of piperazine arabate can be as high as 85% by volume. The
volume yield of benzalkonium cellulose methylcarboxylate
microcapsules can be as high as 40%.
Once encapsulated, core materials are protected from the
environment, but water-soluble core materials may be slowly
released from the microcapsules by suspending the capsules in an
aqueous medium into which the core material can actively diffuse
through the semi-permeable microcapsule walls. In general, if one
holds the nature of the wall-forming reactants constant one finds
highly water-soluble materials are released more rapidly than are
poorly water-soluble core materials and, in general, substances of
low molecular weight are released more rapidly than are substances
of higher molecular weight. Conversion of the microcapsules to
lyocakes and resuspension in aqueous media is preferred.
The utility of these microcapsules as a sustained release device
has been demonstrated with specific reference to a number of drugs
such as the anti-asthmatic drug theophylline in a dialysis system.
Others tested successfully include doxorubicin, niacinamide,
deferoxamine and terbutaline. These are exemplified below with
reference to theophylline.
An unexpected characteristic of the new microcapsules is the
flexibility of the resulting microparticles when hydrated. This
flexibility allows their passage without disruption through
submicron filters routinely utilized for sterilization of
solutions. Submicron filtration does not appear to change
significantly the number or size distribution of the particle
population.
Another unexpected property shown by microcapsules of this
invention is their stability in water and their ability to
encapsulate water. For example, the salt piperazine arabate, one of
the preferred wall-forming components described herein, is itself
soluble in water as may be shown by mixing stoichiometric volumes
of aqueous solutions of piperazine and arabic acid. The piperazine
arabate so formed is quite soluble and may be recovered as a
brittle film from its aqueous solution by evaporation of the water
and, if desired, again dissolved in water. However, when piperazine
arabate is generated as an encapsulating membrane by the
interfacial reaction of stoichiometric amounts of piperazine and
arabic acid as taught herein, the resulting material is in a
metastable, multi-lammelar form which is poorly soluble in water
and which is capable of making stable encapsulations of water or
aqueous solutions.
As a result, in contrast to the microcapsules of U.S. Pat. No.
3,959,457, the piperazine arabate microcapsules of this invention
are stable in 80.degree. C. water and in 0.1 N hydrochloric acid
and 0.1 N sodium hydroxide.
EXAMPLE 1
1.0 g of arabic acid in 20 ml of water was dispersed in 25 ml of a
vigorously stirred 10% solution of sorbitan trioleate in
cyclohexane/chloroform (4:1).
While continuing to stir vigorously, 0.02 g of piperazine in 5 ml
of cyclohexane/chloroform (4:1) was added to the dispersion. When
the addition was completed, stirring was stopped and the vessel was
sealed to prevent evaporation of the solvents. A milky suspension
was observed. After 7 days, the sample was visually examined and
found to contain the following settled percentage volumes of
continuous organic, microcapsules and unencapsulated aqueous
phases, respectively: 26, 73, 1.
In a similar manner, microcapsules were prepared at various ratios
of aqueous to organic phase, ranging from 0.2 to 0.6 volume
fraction aqueous phase.
______________________________________ % % % % % Aqueous Organic
Micro- Unencapsulated Continuous Phase Phase capsules Aqueous Phase
Organic Phase ______________________________________ 20 80 33 0 67
30 70 49 0 51 40 60 73 1 26 50 50 85 5 10 60 40 85 8 7
______________________________________
EXAMPLE 2
The procedure of Example 1 was repeated for varying concentrations
of sorbitan trioleate.
______________________________________ % % % % Sorbitan Micro-
Unencapsulated Continuous Trioleate capsules Aqueous Phase Organic
Phase ______________________________________ 0 2 32 66 5 52 5 43 10
68 2 30 15 72 0 28 20 71 0 29
______________________________________
EXAMPLE 3
Two aqueous solutions containing equal amounts of the drug
theophylline were prepared. Solution A contained the drug
microencapsulated following the teaching of this invention. In
solution B the native drug was directly dissolved. Both solutions
were dialyzed to determine the relative propensities of the
encapsulated and unencapsulated drug to migrate from solution.
In the dialysis system the test solution is pumped in a continuous
loop past a dialysis membrane at a constant flow rate. The same
pump moves a continuous stream of aqueous recipient medium past the
other side of the dialysis membrane and then to an automatic
fraction collector. At timed intervals the fraction collector
positions collection vessels for receipt of aliquots of dialysate
from the recipient stream. Successive aliquots of recipient are
analyzed spectrophotometrically for the concentration of released
material in each.
These data showed that approximately 50% of the initial amount of
unencapsulated theophylline was cleared from the donor stream in
about 4 hours. However, microencapsulation controlled the release
of theophylline so that only about 17% of the initial amount was
released to the recipient stream in the same time period.
EXAMPLE 4
A solution of 0.05 g of sodium carboxymethylcellulose in 10 ml of
water was dispersed in 35 ml of a vigorously stirred 10% solution
of sorbitan trioleate in cyclohexane/chloroform (4:1).
While continuing to stir vigorously, 0.02 g of benzalkonium
chloride in 5 ml of cyclohexane/chloroform (4:1) was added to the
dispersion. When the addition was completed, stirring was stopped
and the vessel was sealed to prevent evaporation of the solvents. A
milky suspension was observed. After 7 days the sample was visually
examined and found to contain the following settled percentage
volumes of continuous organic, microcapsular and unencapsulated
aqueous phases, respectively: 69, 27 and 4.
In similar manner, microcapsules were prepared at various ratios of
aqueous to organic phase, ranging from 0.20 to 0.35 volume fraction
aqueous phase.
______________________________________ Percentage Settled Volumes
of Phases Preparation System Resulting Products Aqueous Organic
Organic Microcapsule Aqueous ______________________________________
20 80 69 27 4 23 77 60 36 4 26 74 58 38 4 29 71 52 40 8 31 69 55 35
10 33 67 60 20 20 35 65 60 10 30
______________________________________
While this invention has been described with reference to specific,
and particularly, preferred embodiments thereof, it is not limited
thereto and the appended claims are intended to be construed to
encompass not only the specific forms and variants of the invention
shown but to such other forms and variants as may be devised by
those skilled in the art without departing from the true spirit and
scope of the invention.
* * * * *